Lipid Signalling Flashcards
Second messengers
Mediate primary signal transfer to effectors
- their net levels determine cellular response
- they eventually degrade
Examples include cAMP, Ca2+ and Phosphoinositoides
- Protein Kinase A (PKA) activity is logarithmic to cAMP levels
Lipid-derived second messenger production
produced in membranes
- e.g. Phospholipase C enzyme release soluble and lipid-attached 2nd messengers in response to diverse inputs
- e.g. Phospholipases D (PLD) & A (PLA) hydrolyse membrane-bound phospholipids to create 2nd messengers
Lipid-derived second messengers include:
- Phosphoinositoides, sphingolipids, GPCR activators and Nuclear Receptor Activators
PIP3
Phosphatidylinositol 3,4,5 Triphosphate
Synthesised by PI 3-kinase (PI3K) to mediate numerous cellular pathways
- It’s recognised by proteins via its Plecktrin Homology (PH) domain
- e.g. Binds to and phosphorylates (activates) Akt: pathway promotes Glucose uptake, glycogen synthesis, anti-lipolysis and anti-apoptosis
Phosphoinocitides (PI) structure
- 2x fatty acyl chains (C18-C20)
- Glycerol backbone
- Inositol sugar attached to terminal glycerol carbon
PIP2
Phosphatidylinositol 4,5 Triphosphate
Regulates multiple cellular responses:
- endocytosis, cytoskeleton and controlling ion flux
- triggers Ca2+ release (used in other signalling pathways)
Phospholipase C (PLC) hydrolyses PIP2 into DAG (diacylglycerol) + PIP3 - DAG binds protein kinase C
Membrane bound PIs
Recruit effector proteins to membrane
- Proteins (ligands) interact with enzymes like G-proteins to trigger signalling
- In turn promotes recruitment of protein kinases and phosphatases (trigger intracellular signalling pathways)
Producing intermediate lipid messengers:
Phosphatidylinositol 3-kinase (PI3K) family
various genes encode catalytic subunits and regulatory subunits
PI modifying enzymes localise in different membranes
Class 1) PI3K localised in plasma membranes and endosomes
Class 2) In Golgi and Secretory pathway
Class 3) Endosomes & Golgi
Class 4) PI4K in Golgi and Endosomes
Different phospholipases cleave phosphoinositol at different points
Phospholipase A2
- produces Lyso-PC + fatty acid
Phospholipase C
- Produces phosphocholine + DAG
Phospholipase D
- Produces choline + PA (phosphatidic acid)
Phosphoinositides binding PH domain
Specificity based on headgroup arrangement of inositol sugar:
- high affinity binding with low dossciation constant
Protein Kinase C in lipid metabolism
various domains (multigene family) enables its function:
C1 domain: binding DAG
C2 domain: binding membranes (in presence of Ca2+)
C3 domain: binding ATP
C4 domain: binding substrate for phosphorylation
Lipid metabolism in inflammation
COX enzymes needed to convert Arachidonic acid into prostaglandins, thromboxane and prostacyclin (key inflammatory molecules)
GPCR (G Protein Coupled Receptor) activators
- Lysophosphatidic Acids (LPAs) and Sphingosine-1-phosphate (S1P) both bind with high affinity
- Platelet Activating Factor binds to PAFP (type of GPCR) to activate platelet aggregation, inflammation and anaphylaxis
- Retinol derivatives (e.g. Vitamin A) bind to rhodopsin (type of GPCR) to regulate visual cycle
Nuclear Activators: Steroid Hormones
Resemble cholesterol and regulate gene expression:
- grouped into 5 classes
1) glucocorticoids
2) mineralocorticoids
3) androgens
4) estrogens
5) progestrogens
Nuclear Activators: Retinol (Vitamin A)
Retinol is broken down into retanoic acid: activataes the Retanoic Acid Receptor (RAR) to control differentiation and proliferation
- binds specific gene expression regulators
